Phosphatidylserine (PS), a membrane phospholipid, is typically localized to the internal surface of the membrane of a healthy cell. Under certain circumstances, PS is also found on the external surface. See Leventis et al., Annu. Rev. Biophys. 2010, 39, 407-27.
More specifically, PS is exposed on the external surface of cancer cells. See Thorpe et al., Breast Cancer Res Treat 1995, 36(2), 237-51; Ran et al., Int. J. Radiat. Oncol. Biol. Phys. 2002, 54(5), 1479-84; and Thorpe, Thromb. Res. 2010, 125 Suppl 2, S134-137. Further, recent studies found that PS exists in tumor vasculatures and tumor-derived microvessels. See Stafford et al., Neoplasia. 2011, 13, 299-308; and Yin et al., Cancer Immunology Research 2013, 1, 1-13. Moreover, in many pathogenic particles such as bacteria and viruses, PS is exposed at high levels on the external surface. See Huang et al., Cancer Res. 2005, 65(10), 4408-16; and White et al., Bioconjug. Chem. 2010, 21(7), 1297-1304. Finally, PS has been found on the outer surface of cells in which cell death pathways have been dysregulated. For example, in addition to cancer, conditions such as neurodegenerative disorders, cardiovascular disease, autoimmune diseases, and metabolic disorders demonstrate surface localization of PS. See Smith et al., Mol. Pharm. 2011, 8(2), 583-90. Thus, PS provides a valuable target for delivery of therapeutic agents for treating the conditions mentioned above.
Protein Annexin V is currently used to deliver therapeutic agents via binding to PS. However, this binding requires high levels of Ca2+, which might activate “scramblases” that could externalize PS in nearby normal cells, resulting in undesired targeting of the normal cells.
There is a need to develop a delivery agent that selectively associates with disease-relevant PS to achieve site-specific delivery of a therapeutic agent.